Haloperidol disrupts Akt signalling to reveal a phosphorylation-dependent regulation of pro-apoptotic Bcl-XS function.
The antipsychotic drug haloperidol is still used to treat psychosis and "agitation", often with devastating consequences, particularly in geriatric and pre-demented patients. Cytotoxicity induced by haloperidol has been associated with induction of Bcl-XS, a pro-apoptotic member of the Bcl-2 family, as well as with modulation of the Akt pro-survival pathway. Using preneuronal PC12 and primary neuronal cultures, we show that haloperidol inactivates Akt. This induces the dephosphorylation of serine residues in Bcl-XS and promotes its association with the mitochondrial voltage-dependent anion channel (VDAC), as well as with cytochrome c- and caspase-3-dependent events. These events are sensitive to expression of constitutively active Akt. Mutation of Serine106 (Ser106), which is flanked by a putative Akt motif, hinders the association of the Bcl-XS protein with Akt, but promotes its association with VDAC. The dephosphorylation mimic, Bcl-XS(Ser106Ala), induces caspase-dependent PC12 and neuronal cell apoptosis. In contrast, Bcl-XS(Ser106Ala) induces a significant loss of VDAC expression, and cytochrome c- and caspase-independent toxicity in the non-neuronal HEK293A cells. We link haloperidol and Akt to Bcl-XS-sensitive toxicity via cell line-dependent mitochondrial events centering on VDAC. This clearly mitigates the chronic use of haloperidol in neuropsychiatric populations, but supports its use as a potential acute therapeutic in cancer, where apoptosis is desirable.
Wei
Zelan
Z
Cell Signalling Laboratory, Neuropsychiatry Research Unit, University of Saskatchewan, Saskatoon (SK), Canada.
Qi
Ji
J
Dai
Yunxiu
Y
Bowen
Wayne D
WD
Mousseau
Darrell D
DD
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D006220:Haloperidol / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016716:PC12 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism / Q000502:physiology; D051020:bcl-X Protein / Q000378:metabolism*
D014150:Antipsychotic Agents; D050994:Voltage-Dependent Anion Channels; D051020:bcl-X Protein; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D006220:Haloperidol